Radiation therapy is used to treat approximately 50% of all patients with cancer. To improve the cure rate with radiation therapy and to decrease the short- and long-term side effects of radiation, we have received multiple NIH grants to study radiation biology in small animals. Although major technological improvements in target localization and radiation delivery have occurred in the clinic, this technology is not available at Duke University for our pre-clinical experiments. The inability to obtain images of the radiation target (tumor or normal organ) and to deliver radiation to a focused volume has been a major barrier to advancing radiation oncology research. To improve our ability to carry out clinically meaningful research in radiation biology, we request a shared instrument that combines multiple on-board imaging capabilities, such as micro-CT, with conformal small beam radiation therapy. This technology is now being used to treat patients with image-guided radiation therapy. The proposed instrument uses state-of-the-art technology for small animals that rigorously simulates the planning and treatment conditions of our patients. We propose to use this technology to investigate (1) mechanisms of tumor control and (2) normal tissue injury by radiation therapy. We will utilize the on-board imaging and the custom collimators to safely deliver large doses of radiation with high precision and accuracy to dissect mechanisms of tumor control. This approach will allow us to study the clinically meaningful endpoint of tumor cure. Moreover, the ability to image small animals and localize the tumor target before each treatment will facilitate fractionated radiation therapy schedules for small animals, which are routinely used to treat patients in the clinic. The instrument will also allow us to have the unprecedented ability to focus radiation therapy on a single organ, or even part of an organ, to study mechanisms of normal tissue injury. This approach will avoid multi-organ injury by the radiation treatment and will thereby facilitate studies of radiation-induced normal tissue injury in small animals. In summary, this technology offers a dramatic improvement in our ability to study fundamental radiation biology questions using the same technology with which we treat patients. Combining this novel instrument with the extensive expertise in radiation biology at Duke will bring about new discoveries and will facilitate their translation into improved cancer therapy.